Iron (iii) citrate, substantially free of beta-iron hydroxide oxide

ABSTRACT

This invention provides a method for producing high-purity iron(III) citrate substantially free of beta-iron hydroxide oxide, high-purity iron(III) citrate substantially free of beta-iron hydroxide oxide, and medical uses thereof.

TECHNICAL FIELD

The present invention relates to high-purity iron(III) citrate and amethod for producing the same.

BACKGROUND ART

Patent Document 1 describes that a ferric organic compound involving aniron(III) citrate of a specific type is useful for treatment ofhyperphosphatemia or other diseases.

PRIOR ART DOCUMENT Patent Document

-   Patent Document 1: JP Patent Publication (Kohyo) No. 2006-518391 A

SUMMARY OF THE INVENTION Object to be Attained by the Invention

The present invention is intended to provide a method for producinghigh-purity iron(III) citrate substantially free of beta-iron hydroxideoxide, high-purity iron(III) citrate substantially free of beta-ironhydroxide oxide, and medical uses thereof.

Means for Attaining the Object

The present inventors studied a variety of means for attaining the aboveobject. As a result, the present inventors have discovered that suchobject could be attained by modifying the conditions used in connectionwith the method described in Patent Document 1 for bringing ferricchloride into contact with sodium hydroxide, thereby completing thepresent invention.

Specifically, the present invention is summarized as follows.

(1) High-purity iron(III) citrate substantially free of beta-ironhydroxide oxide, wherein the beta-iron hydroxide oxide content is lessthan 6% by weight based on the total weight thereof.

(2) The high-purity iron(III) citrate according to (1), wherein thebeta-iron hydroxide oxide content is less than 2.5% by weight.

(3) The high-purity iron(III) citrate according to (1), wherein thebeta-iron hydroxide oxide content is less than 1.0% by weight.

(4) The high-purity iron(III) citrate according to any of (1) to (3),wherein the molar ratio of iron(III) to citric acid is from 1:0.75 to1:1.10.

(5) The high-purity iron(III) citrate according to (4), wherein themolar ratio of iron(III) to citric acid is from 1:0.80 to 1:0.92.

(6) The high-purity iron(III) citrate according to any of (1) to (5),wherein the percentage of iron(III) citrate dissolved within 15 minutesis 80% or more in dissolution testing conducted with the use of thefirst fluid of dissolution testing of the Japanese Pharmacopoeia,Fifteenth Edition as a test liquid via the paddle method at 100 rpm inaccordance with the Japanese Pharmacopoeia, Fifteenth Edition.

(7) A pharmaceutical composition comprising, as an active ingredient,the high-purity iron(III) citrate according to any of (1) to (6).

(8) An agent for treatment or amelioration of hyperphosphatemiacomprising, as an active ingredient, the high-purity iron(III) citrateaccording to any of (1) to (6).

(9) A phosphate binder comprising, as an active ingredient, thehigh-purity iron(III) citrate according to any of (1) to (6).

(10) An agent for reducing serum phosphorus level comprising, as anactive ingredient, the high-purity iron(III) citrate according to any of(1) to (6).

(11) Powder of the high-purity iron(III) citrate according to any of (1)to (6), which has an amorphous structure.

(12) Powder of the high-purity iron(III) citrate according to any of (1)to (6), which has a specific surface area of 20 to 45 m²/g.

(13) Powder of the high-purity iron(III) citrate according to (11),which has a specific surface area of 20 to 45 m²/g.

(14) A pharmaceutical composition comprising, as an active ingredient,the powder according to any of (11) to (13).

(15) An agent for treatment or amelioration of hyperphosphatemiacomprising, as an active ingredient, the powder according to any of (11)to (13).

(16) A method for producing iron(III) citrate comprising:

a step of forming an iron-containing precipitate comprising bringingferric chloride into contact with sodium hydroxide for a short period oftime at low temperature in an aqueous medium to form an iron-containingprecipitate;

a step of generating an aqueous solution of iron(III) citrate comprisingbringing citric acid into contact with the iron-containing precipitatein an aqueous medium and generating an aqueous solution of iron(III)citrate via heating; and

a step of precipitating iron(III) citrate comprising bringing theaqueous solution of iron(III) citrate into contact with an organicsolvent to precipitate the iron(III) citrate.

(17) The method according to (16), wherein the step of formingiron-containing precipitate comprises bringing ferric chloride intocontact with sodium hydroxide within 2 hours at a liquid temperature of0° C. to 10° C.

(18) The method according to (16) or (17), wherein the step ofgenerating an aqueous solution of iron(III) citrate comprises bringingcitric acid into contact with the iron-containing precipitate at aliquid temperature of 60° C. to 100° C.

(19) The method according to any of (16) to (18), wherein theiron-containing precipitate is ferrihydride.

(20) Iron(III) citrate produced by the method according to any of (16)to (19).

(21) A pharmaceutical composition comprising, as an active ingredient,the iron(III) citrate according to (20).

(22) An agent for treatment or amelioration of hyperphosphatemiacomprising, as an active ingredient, the iron(III) citrate according to(20).

(23) A phosphate binder comprising, as an active ingredient, theiron(III) citrate according to (20).

(24) An agent for reducing serum phosphorus level comprising, as anactive ingredient, the iron(III) citrate according to (20).

(25) Powder of the iron(III) citrate according to (20), which has anamorphous structure.

(26) Powder of the iron(III) citrate according to (20), which has aspecific surface area of 20 to 45 m²/g.

(27) Powder of the iron(III) citrate according to (25), which has aspecific surface area of 20 to 45 m²/g.

(28) A pharmaceutical composition comprising, as an active ingredient,the powder according to any of (25) to (27).

(29) An agent for treatment or amelioration of hyperphosphatemiacomprising, as an active ingredient, the powder according to any of (25)to (27).

(30) The pharmaceutical composition according to (7), (14), (21), or(28) for use in treatment of hyperphosphatemia.

(31) A high-purity iron(III) complex with citric acid and watersubstantially free of beta-iron hydroxide oxide, wherein the beta-ironhydroxide oxide content is less than 6% by weight based on the totalweight thereof.

(32) The high-purity iron(III) complex with citric acid and wateraccording to (31), wherein the beta-iron hydroxide oxide content is lessthan 2.5% by weight.

(33) The high-purity iron(III) complex with citric acid and wateraccording to (31), wherein the beta-iron hydroxide oxide content is lessthan 1.0% by weight.

(34) The high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (33), wherein the molar ratio of iron(III)to citric acid is from 1:0.75 to 1:1.10.

(35) The high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (33), wherein the molar ratio of iron(III)to citric acid is from 1:0.80 to 1:0.92.

(36) The high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (33), which has a specific surface area of20 to 45 m²/g and an amorphous structure.

(37) The high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (36), wherein the percentage of thehigh-purity iron(III) complex dissolved within 15 minutes is 80% or morein dissolution testing conducted with the use of the first fluid ofdissolution testing of the Japanese Pharmacopoeia, Fifteenth Edition asa test liquid via the paddle method at 100 rpm according to the JapanesePharmacopoeia, Fifteenth Edition.

(38) A pharmaceutical composition comprising, as an active ingredient,the high-purity iron(III) complex with citric acid and water accordingto any of (31) to (37).

(39) An agent for treatment or amelioration of hyperphosphatemiacomprising, as an active ingredient, the high-purity iron(III) complexwith citric acid and water according to any of (31) to (37).

(40) A phosphate binder comprising, as an active ingredient, thehigh-purity iron(III) complex with citric acid and water according toany of (31) to (37).

(41) An agent for reducing serum phosphorus level comprising, as anactive ingredient, the high-purity iron(III) complex with citric acidand water according to any of (31) to (37).

(42) A method for producing an iron(III) complex with citric acid andwater comprising:

a step of forming an iron-containing precipitate comprising bringingferric chloride into contact with sodium hydroxide for a short period oftime at low temperature in an aqueous medium to form an iron-containingprecipitate;

a step of generating an aqueous solution of the iron(III) complex withcitric acid and water comprising bringing citric acid into contact withthe iron-containing precipitate in an aqueous medium and generating anaqueous solution of the iron(III) complex with citric acid and water viaheating; and

a step of precipitating an iron(III) complex with citric acid and watercomprising bringing an aqueous solution of the iron(III) complex withcitric acid and water into contact with an organic solvent toprecipitate the iron(III) complex with citric acid and water.

(43) The method according to (42), wherein the step of formingiron-containing precipitate comprises bringing ferric chloride intocontact with sodium hydroxide within 2 hours at a liquid temperature of0° C. to 10° C.

(44) The method according to (42) or (43), wherein the step ofgenerating an aqueous solution of the iron(III) complex with citric acidand water comprises bringing citric acid into contact with theiron-containing precipitate at a liquid temperature of 60° C. to 100° C.

(45) The method according to any of (42) to (44), wherein theiron-containing precipitate is ferrihydride.

(46) An iron(III) complex with citric acid and water produced by themethod according to any of (42) to (45).

(47) A pharmaceutical composition comprising, as an active ingredient,the iron(III) complex with citric acid and water according to (46).

(48) The pharmaceutical composition according to (38) or (47) for use intreatment of hyperphosphatemia.

(49) An agent for treatment or amelioration of hyperphosphatemiacomprising, as an active ingredient, the iron(III) complex with citricacid and water according to (46).

(50) An agent for treating hyperphosphatemia or phosphate bindercomprising, as an active ingredient, the iron(III) complex with citricacid and water according to (46).

(51) An agent for treating hyperphosphatemia or for reducing serumphosphorus level comprising, as an active ingredient, the iron(III)complex with citric acid and water according to (46).

(52) A method for treatment or amelioration of hyperphosphatemiacomprising administering an effective amount of the high-purityiron(III) citrate according to any of (1) to (6) or the iron(III)citrate according to (20) to a patient or a test subject in needthereof.

(53) Use of the high-purity iron(III) citrate according to any of (1) to(6) or the iron(III) citrate according to (20) in the manufacture of amedicament for treatment or amelioration of hyperphosphatemia.

(54) The high-purity iron(III) citrate according to any of (1) to (6) orthe iron(III) citrate according to (20) for use as a medicament.

(55) The high-purity iron(III) citrate according to any of (1) to (6) orthe iron(III) citrate according to (20) for use in treatment oramelioration of hyperphosphatemia.

(56) A method for treatment or amelioration of hyperphosphatemiacomprising administering an effective amount of powder of thehigh-purity iron(III) citrate according to any of (11) to (13) or powderof the iron(III) citrate according to any of (25) to (27) to a patientor a test subject in need thereof.

(57) Use of the powder of the high-purity iron(III) citrate according toany of (11) to (13) or powder of the iron(III) citrate according to anyof (25) to (27) in the manufacture of a medicament for treatment oramelioration of hyperphosphatemia.

(58) Powder of the high-purity iron(III) citrate according to any of(11) to (13) or powder of the iron(III) citrate according to any of (25)to (27) for use as a medicament.

(59) Powder of the high-purity iron(III) citrate according to any of(11) to (13) or powder of the iron(III) citrate according to any of (25)to (27) for use in treatment or amelioration of hyperphosphatemia.

(60) A method for treatment or amelioration of hyperphosphatemiacomprising administering an effective amount of the high-purityiron(III) complex with citric acid and water according to any of (31) to(37) or the iron(III) complex with citric acid and water according to(46) to a patient or a test subject in need thereof.

(61) Use of the high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (37) or the iron(III) complex with citricacid and water according to (46) in the manufacture of a medicament fortreatment or amelioration of hyperphosphatemia.

(62) The high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (37) or the iron(III) complex with citricacid and water according to (46) for use as a medicament.

(63) The high-purity iron(III) complex with citric acid and wateraccording to any of (31) to (37) or the iron(III) complex with citricacid and water according to (46) for use in treatment or amelioration ofhyperphosphatemia.

This description includes part or all of the contents as disclosed inthe descriptions and/or drawings of Japanese Patent Application No.2011-007887 and U.S. Provisional Patent Application No. 61/438,303,which are priority documents of the present application.

Effects of the Invention

The present invention can provide a method for producing high-purityiron(III) citrate substantially free of beta-iron hydroxide oxide,high-purity iron(III) citrate substantially free of beta-iron hydroxideoxide, and medical uses thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the IR spectrum of the iron(III) citrate of Example 4.

FIG. 2 shows the X-ray diffraction spectrum of the iron(III) citratepowder of Example 4.

FIG. 3 shows the results of comparison of dissolution profilesdetermined with the use of the first fluid (pH 1.2) of dissolutiontesting of the Japanese Pharmacopoeia for the iron(III) citratesaccording to Comparative Examples 1, 11, and 12 and Examples 4, 5, 6, 7,8, and 9.

FIG. 4 shows the average amount of phosphorus absorbed and the averageamount of phosphorus excreted into the urine (mg/day) of a control groupand of a test group (Example 1) determined via a test of phosphorusabsorption inhibition using rats.

EMBODIMENTS FOR CARRYING OUT THE INVENTION 1. Iron(III) Citrate

The present invention relates to high-purity iron(III) citratesubstantially free of beta-iron hydroxide oxide.

The term “iron(III) citrate” used herein refers to a complex ofiron(III) (Fe(III)) with citric acid, and an embodiment thereof is acomplex represented by the following molecular formula:Fe.x(C₆H₈O₇).y(H₂O). In the above molecular formula, x is preferablyfrom 0.75 to 1.10, more preferably from 0.78 to 0.95, particularlypreferably from 0.80 to 0.92, and most preferably from 0.81 to 0.91.According to another embodiment, x is preferably from 0.75 to 1.15, andmore preferably from 0.80 to 1.10. y is preferably from 1.8 to 3.2, morepreferably from 2.4 to 3.1, and particularly preferably from 2.7 to 3.1.Also, the molar ratio of iron(III) to citric acid is preferably from1:0.75 to 1:1.10, more preferably from 1:0.78 to 1:0.95, particularlypreferably from 1:0.80 to 1:0.92, and most preferably from 1:0.81 to1:0.91. According to another embodiment, the molar ratio of iron(III) tocitric acid is preferably from 1:0.75 to 1:1.15, and more preferablyfrom 1:0.80 to 1:1.10. The molar ratio of iron(III) to water ispreferably from 1:1.8 to 1:3.2, more preferably from 1:2.4 to 1:3.1, andparticularly preferably from 1:2.7 to 1:3.1.

As described in detail below, the present inventors have discovered thatpreparation of a complex of iron(III) with citric acid according to themethod described in Patent Document 1 would occasionally lead toinclusion of beta-iron hydroxide oxide ((β-FeOOH), which is hardlysoluble in water, as a by-product in the complex.

In contrast, the iron(III) citrate of the present invention produced bythe method described below is substantially free of beta-iron hydroxideoxide. Thus, the present invention provides high-purity iron(III)citrate substantially free of beta-iron hydroxide oxide. According to anembodiment of the present invention, the iron(III) citrate is ahigh-purity iron(III) complex with citric acid and water substantiallyfree of beta-iron hydroxide oxide. Thus, the iron(III) citrate of thepresent invention encompasses a high-purity iron(III) complex withcitric acid and water substantially free of beta-iron hydroxide oxide.In the high-purity iron(III) citrate according to the present invention,the beta-iron hydroxide oxide content is preferably less than 6% byweight, more preferably 2.5% or less by weight, particularly preferably1.0% or less by weight, and most preferably 0 to 1% by weight, relativeto the total weight. In this description, the term “substantially freeof beta-iron hydroxide oxide” refers to condition in which the beta-ironhydroxide oxide content is within the range described above, and theterm “high-purity iron(III) citrate” refers to iron(III) citrate with abeta-iron hydroxide oxide content that is within the range describedabove.

It should be noted that the beta-iron hydroxide oxide content iniron(III) citrate can be determined via, for example, but is not limitedto, powder X-ray diffraction.

According to an embodiment of the present invention, the iron(III)citrate and high-purity iron(III) citrate each have a specific surfacearea of, for example, 20 m²/g or higher, preferably 20 to 45 m²/g, andmore preferably 20 to 40 m²/g.

A specific surface area can be measured by, for example, but is notlimited to, BET surface area measurement via nitrogen gas adsorption(relative pressure: 0.05 to 0.3).

According to an embodiment of the present invention, the iron(III)citrate and high-purity iron(III) citrate are amorphous, and preferablyamorphous powders. Thus, the present invention also relates to anamorphous form or amorphous powder of iron(III) citrate or high-purityiron(III) citrate having features described above and below. The term“amorphous form” used herein refers to a halo pattern having diffusivemaxima observed via powder X-ray diffraction.

In addition, the percentage of the iron(III) citrate and that ofhigh-purity iron(III) citrate according to the present inventiondissolved within 15 minutes are each 80% or more, preferably 85% ormore, more preferably 90% or more, and most preferably 95% or more, indissolution testing conducted with the use of the first fluid ofdissolution testing of the Japanese Pharmacopoeia, Fifteenth Edition asa test liquid via the paddle method at 100 rpm according to the JapanesePharmacopoeia, Fifteenth Edition.

Because of such features, the iron(III) citrate and high-purityiron(III) citrate according to the present invention can exert excellentdissolution properties.

2. Method for Producing Iron(III) Citrate

The present invention also relates to a method for producing iron(III)citrate. The method of the present invention at least comprises a stepof forming an iron-containing precipitate, a step of generating anaqueous solution of iron(III) citrate, and a step of precipitatingiron(III) citrate. These steps are described below.

2-1. Step of Forming Iron-Containing Precipitate

This step is intended to form an iron-containing precipitate by bringingferric chloride into contact with sodium hydroxide in an aqueous medium.An example of “contact” is dropwise addition of an aqueous solution ofsodium hydroxide to an aqueous solution of ferric chloride, but notlimited thereto.

The iron-containing precipitate formed in this step preferably comprisesferrihydride as a main component. It is more preferable that suchiron-containing precipitate comprise ferrihydride as a main componentand be substantially free of beta-iron hydroxide oxide.

Ferric chloride used in this step may be in the form of an anhydrate orhydrate thereof. Alternatively, it may be in the form of an aqueoussolution thereof. Ferric chloride of any form can be used in the methodof the present invention.

An aqueous medium used in this step is preferably water. In such a case,an aqueous solution containing an iron-containing precipitate, orpreferably a precipitate containing ferrihydride as a main component, isgenerated in this step. Such aqueous medium is preferably substantiallyfree of components other than citric acid and the precipitate describedabove.

Ferric chloride and sodium hydroxide used in this step may have a levelof purity that is commonly employed in the art. The molar ratio offerric chloride to sodium hydroxide is preferably from 1:1 to 1:5, andmore preferably from 1:2 to 1:4.

The concentration of iron(III) in ferric chloride in the solutiongenerated in this step is preferably 2% to 6% by weight, and morepreferably 3% to 5% by weight. Sodium hydroxide content is preferably 5%to 15% by weight, and more preferably 9% to 11% by weight.

The present inventors studied conditions in which beta-iron hydroxideoxide formation would be inhibited. As a result, The present inventorshave discovered that an iron-containing precipitate comprisingferrihydride as a main component and substantially free of beta-ironhydroxide oxide could be formed by bringing ferric chloride into contactwith sodium hydroxide for a short period of time at a low temperature.

In this step, the duration during which ferric chloride is allowed to bein contact with sodium hydroxide is preferably within 3 hours, morepreferably within 2 hours, further preferably within 1 hour, andparticularly preferably within 30 minutes. It is preferable that ferricchloride be brought into contact with sodium hydroxide at a temperature(liquid temperature) of 15° C. or lower, more preferably 10° C. orlower, and particularly preferably from 0° C. to 10° C.

In this step, accordingly, ferric chloride is preferably brought intocontact with sodium hydroxide within 3 hours at a liquid temperature of15° C. or lower, at 10° C. or lower, or from 0° C. to 10° C., morepreferably within 2 hours at a liquid temperature of 15° C. or lower,further preferably within 2 hours at a liquid temperature of 10° C. orlower, particularly preferably within 2 hours at a liquid temperature of0° C. to 10° C., and most preferably within 1 hour at a liquidtemperature of 0° C. to 10° C.

The final pH of a mixture obtained by bringing ferric chloride intocontact with sodium hydroxide in this step is preferably from 8 to 10.

By performing this step under such conditions, formation of beta-ironhydroxide oxide can be suppressed, and a precipitate substantially freeof beta-iron hydroxide oxide can be formed.

2-2. Step of Washing

The method of the present invention may comprise a step of washingcomprising washing an iron-containing precipitate 1 to 3 times prior tothe step of generating an aqueous solution of iron(III) citratedescribed below.

In this step, it is preferable that an iron-containing precipitate iswashed with an aqueous medium. Such aqueous medium is preferablypurified water that is substantially free of other ingredients.

This step is preferably carried out at 10° C. to 30° C.

By performing this step under such conditions, the purity of resultingiron(III) citrate can be enhanced.

2-3. Step of Generating Aqueous Solution of Iron(III) Citrate

This step is intended to generate an aqueous solution of iron(III)citrate by bringing citric acid into contact with the iron-containingprecipitate obtained by the above step in an aqueous medium. An exampleof “contact” is a reaction between an iron-containing precipitate and anaqueous solution of citric acid, but not limited thereto.

An aqueous medium used in this step is preferably water. In such a case,an aqueous solution of iron(III) citrate is generated in this step. Suchaqueous medium is preferably substantially free of components other thancitric acid and the precipitate described above.

Citric acid used in this step may have a level of purity that iscommonly employed in the art. The molar ratio of iron(III) to citricacid contained in the iron-containing precipitate is preferably from1:1.0 to 1:1.5, and more preferably from 1:1.2 to 1:1.3. According toanother embodiment, the molar ratio of iron(III) to citric acidcontained in the iron-containing precipitate is preferably from 1:1.0 to1:3.0, and more preferably from 1:1.0 to 1:1.6.

In the solution obtained in this step, the concentration of citric acidis preferably from 10% to 40% by weight, and more preferably 20% to 30%by weight.

In this step, citric acid is brought into contact with theiron-containing precipitate in a medium to generate a mixture, and theresulting mixture is then heated to generate an aqueous solution ofiron(III) citrate. In this step, heating is preferably carried out at aliquid temperature of 60° C. to 100° C., and more preferably at a liquidtemperature of 70° C. to 90° C. The heating duration is preferably from1 to 3 hours, and more preferably from 1.5 to 2.5 hours.

In this step, accordingly, it is particularly preferable that an aqueoussolution of iron(III) citrate be generated by heating the aforementionedmixture at the liquid temperature described above for 1 to 3 hours.

By performing this step under such conditions, an aqueous solutioncontaining iron(III) citrate can be generated at a high yield.

2-4. Step of Precipitating Iron(III) Citrate

This step is intended to precipitate iron(III) citrate by bringing theaqueous solution of iron(III) citrate into contact with an organicsolvent.

An example of an organic solvent that can be used in this step is, butis not limited to, a water-miscible organic solvent, such as acetone. Anorganic solvent is preferably acetone or hydrous acetone.

An organic solvent used in this step may have a level of purity that iscommonly employed in the art. The amount of an organic solvent used ispreferably 300 to 500 parts by weight, and more preferably 350 to 450parts by weight, relative to 100 parts by weight of the aqueous solutionof iron(III) citrate.

In this step, the aqueous solution of iron(III) citrate is brought intocontact with an organic solvent under the above conditions toprecipitate the iron(III) citrate. In this step, the precipitationtemperature is preferably between 15° C. and 35° C., and more preferablybetween 20° C. and 30° C. The duration of precipitation is preferablyfrom 0.5 to 2 hours, and more preferably from 0.5 to 1 hour.

The iron(III) citrate obtained by the above method may be subjected toan application of interest in that state. Alternatively, precipitatediron(III) citrate may be further dried. For example, drying can becarried out by the method described in Patent Document 1.

By performing this step under such conditions, high-purity iron(III)citrate can be precipitated at a high yield.

3. Medical Use of Iron(III) Citrate 3-1. Pharmaceutical Composition

A pharmaceutical composition comprising, as an active ingredient, theiron(III) citrate of the present invention can be administered to ahuman and a non-human animal having diseases or disorders describedbelow in vivo. It can be administered to a human a pharmaceuticalcomposition or pharmaceutical formulation in a form described below.When such pharmaceutical composition is administered to a non-humananimal, preferable examples thereof include, but are not limited to, amouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse,sheep, and monkey.

Administration of the pharmaceutical composition or pharmaceuticalformulation of the present invention to the target (a patient or testsubject) enables treatment or amelioration of diseases or disordersdescribed below. Accordingly, the present invention relates to theiron(III) citrate for use as a medicament. In addition, the presentinvention provides a method for treatment or amelioration of diseases ordisorders described below comprising administering the pharmaceuticalcomposition or pharmaceutical formulation of the present invention tothe patient or test subject.

For example, the pharmaceutical composition of the present invention canbe used in inhibition of absorption of phosphate ingested by a patientor in treatment or amelioration of hyperphosphatemia, but are notlimited thereto. Accordingly, the present invention relates to theiron(III) citrate for use in treatment or amelioration ofhyperphosphatemia. In addition, the present invention provides an agentfor treatment or amelioration of hyperphosphatemia comprising, as anactive ingredient, the iron(III) citrate. Also, the present inventionprovides an agent for reducing serum phosphorus level comprising, as anactive ingredient, the iron(III) citrate.

The iron(III) citrate of the present invention has a large specificsurface area and it thus has a high capacity for phosphorus adsorption.Accordingly, the present invention provides a phosphate bindercomprising, as an active ingredient, the iron(III) citrate of thepresent invention.

Use of the pharmaceutical composition or pharmaceutical formulationaccording to the present invention enables treatment or amelioration ofthe diseases or disorders described above. The term “treatment ofhyperphosphatemia” used herein is also defined as “amelioration ofhyperphosphatemia.” For example, the term refers to reduction of theserum phosphorus level to 3.5 to 6.0 mg/dL, although it is not limitedthereto.

3-2. Pharmaceutical Formulation

The iron(III) citrate produced by the method of the present invention;i.e., a pharmaceutical composition comprising, as an active ingredient,high-purity iron(III) citrate of the present invention, may beadministered to a subject in the form of the pharmaceutical compositionalone. Alternatively, high-purity iron(III) citrate of the presentinvention can be provided in the form of a medicament (e.g., apharmaceutical formulation) comprising such compound in combination withat least one member selected from among a pharmaceutically acceptablecarrier, an excipient, a disintegrator, a binder, a fluidizing agent, adiluent, a filler, a buffer, an adjuvant, a stabilizer, a preservative,a lubricant, a solvent, a solubilizer, a suspending agent, anisotonizing agent, a soothing agent and other materials known in theart, and, according to need, other drugs. Therefore, the presentinvention not only provides pharmaceutical compositions described above.The present invention also provides a method for producing a medicamentcomprising mixing high-purity iron(III) citrate of the present inventionwith at least one member selected from among a pharmaceuticallyacceptable carrier, an excipient, a disintegrator, a binder, afluidizing agent, a diluent, a filler, a buffer, an adjuvant, astabilizer, a preservative, a lubricant, a solvent, a solubilizer, asuspending agent, an isotonizing agent, a soothing agent and othermaterials known in the art, and, according to need, other drugs.

Also, the present invention provides use of high-purity iron(III)citrate of the present invention in the manufacture of a medicament fortreatment or amelioration of the diseases or disorders described above.

The term “pharmaceutically acceptable substance” used herein refers to acompound, material, composition, and/or dosage form, which yields anadequate benefit/risk ratio within the scope of appropriate medicaldecision, which does not cause excessive toxicity, stimulation, allergicreactions, or complications, and which is suitable for use while incontact with tissue of a subject (e.g., a human). Since a carrier, anexcipient, and the like can be present together with other ingredientsof a pharmaceutical formulation, such substance should be “acceptable.”

A pharmaceutical formulation can be adequately provided in unit dosageform and it can be prepared by any method well-known in the field ofpharmaceutical technology. Such method comprises a step of mixinghigh-purity iron(III) citrate of the present invention with at least oneauxiliary ingredient (e.g., a carrier). In general, a pharmaceuticalformulation is prepared by homogeneously and coherently mixing an activecompound with a finely ground solid carrier and/or a liquid carrier andthen generating a product, according to need.

Examples of forms of pharmaceutical formulations (dosage forms) include,but are not limited to, oral formulations, such as tablets, capsules,granules, powders, troches, syrup agents, emulsions, and suspendingagents.

Tablets can be produced by optionally adding to high-purity iron(III)citrate of the present invention at least one auxiliary ingredientdescribed above by a conventional means, such as compression or molding.Compressed tablets can be produced by mixing high-purity iron(III)citrate of the present invention with at least one member selected fromamong a binder (e.g., povidone, gelatin, acacia gum, sorbitol,Tragacanth, or hydroxypropyl methylcellulose), a filler or diluent(e.g., microcrystalline cellulose or lactose), a lubricant (e.g.,calcium stearate, talc, or silica), a disintegrator (e.g., crospovidone,sodium carboxymethyl starch, or crosslinked carboxymethylcellulosesodium), a surfactant, a powder, or wetting agent (e.g., sodium laurylsulfate), and a preservative (e.g., methyl p-hydroxybenzoate, propylp-hydroxybenzoate, or sorbic acid), according to need, and compressingthe resultant with a suitable machine. Tablets may be optionally coatedor incised. Alternatively, tablets may be prepared so as to achievesustained release or controlled release of iron(III) citrate containedtherein, for example. Enteric coating may be optionally applied totablets, so that iron(III) citrate can be released at a region of thegastrointestinal tract other than the stomach.

3-3. Treatment Method

When the pharmaceutical composition or pharmaceutical formulation of thepresent invention is used in treatment or amelioration of the diseasesor disorders described above, an adequate dose of high-purity iron(III)citrate of the present invention may differs for each patient. Ingeneral, a dose is selected so as to achieve a local concentration thatrealizes desired effects without substantially causing any harmful sideeffects at a site of interest. A dose selected herein is not limited.For example, it depends on various factors, including activity ofiron(III) citrate, the administration route, the administration time,the discharge speed, the duration of treatment, other drugs to be usedin combination therewith, and age, gender, body weight, pathologicalconditions, general health conditions, and anamnesis of a patient.

In vivo administration can be continuously or intermittently (e.g.,divisional administration at adequate intervals) carried out with asingle dose throughout the entire course of treatment. Administrationcan be implemented once or several times at dosage levels and patternsthat are selected by a physician who provides treatment. When it isorally administered to an adult patient, for example, a suitable dose ofiron(III) citrate is generally about 1 g to 8 g per day. Such dose canbe administered once or a plurality of times.

EXAMPLES

Hereafter, the present invention is described in greater detail withreference to the examples. It should be noted that the technical scopeof the present invention is not limited to these examples.

1. Preparation of Iron(III) Citrate Example 1 Step of FormingIron-Containing Precipitate

An aqueous solution of ferric chloride (60.5 kg, 6.7 kg in terms ofFe³⁺, 120.0 mol) was introduced into a reaction vessel and diluted with102.9 kg of purified water to obtain an aqueous solution of ferricchloride containing 4.1% by weight of Fe³⁺. The aqueous solution offerric chloride was cooled to a liquid temperature of 0° C. to 5° C. Anaqueous solution of 10% by weight of NaOH (139.6 kg) that had beencooled to 0° C. to 5° C. in advance was added dropwise to the aqueoussolution of ferric chloride over a period of 120 minutes whilemaintaining the liquid temperature at 0° C. to 4.2° C., and the final pHlevel was adjusted to 9.05. After the completion of dropwise addition,the obtained mixture was agitated at 1.6° C. to 3.8° C. (liquidtemperature) for 1 hour. The pH level of the mixture was found to bebetween 8.0 and 10.0.

Step of Washing

The mixture obtained in the step above was washed with 120 kg ofpurified water with filtration. An iron-containing crude precipitatemainly composed of ferrihydride separated via filtration (i.e., a wetsolid (1), 70.52 kg) was agitated and washed in 162.7 kg of purifiedwater for 55 minutes. The suspension was filtered again to obtain aniron-containing precipitate mainly composed of ferrihydride (i.e., a wetsolid (2), 53.26 kg).

Step of Generating Aqueous Solution of Iron(III) Citrate

Citric acid (28.9 kg, 150.5 mol) was dissolved in 38.74 kg of purifiedwater to prepare an aqueous solution of citric acid (67.64 kg). The wetsolid (2) obtained in the step above (53.26 kg) and the aqueous solutionof citric acid above (67.64 kg) were introduced into a reaction vessel,and the mixture was prepared via slow agitation at room temperature(about 25° C.) for 70 minutes at an agitation speed of about 67 rpm.Subsequently, the mixture was slowly heated to a temperature (liquidtemperature) of 80° C. in such a manner that the difference between thetemperature (liquid temperature) of the mixture and the externaltemperature was between 0° C. and 15° C. Thereafter, the mixture wasagitated at a liquid temperature of 80.1° C. to 84.0° C. for 120 minutesto dissolve the iron-containing precipitate mainly composed offerrihydride. After such dissolution had been confirmed, the mixture wascooled to a liquid temperature of 20° C. to 30° C. Insoluble material inthe resulting mixture was removed by filtration to obtain an aqueoussolution of iron(III) citrate (118.0 kg).

Step of Precipitating Iron(III) Citrate

Acetone (471.8 kg, 95% by weight) (i.e., acetone containing 5% water byweight) was introduced into a reaction vessel. The aqueous solution ofiron(III) citrate obtained in the step above (118.0 kg) was addeddropwise to 95% by weight of acetone in the reaction vessel over aperiod of 25 minutes with agitation. After the completion of dropwiseaddition, the obtained mixture was agitated at a liquid temperature of21.1° C. to 22.2° C. for 40 minutes. The resulting mixture was filteredto obtain an iron(III) citrate-containing precipitate (i.e., a wet solid(3), 74.08 kg). The obtained wet solid (3) (74.08 kg) was dried toobtain high-purity iron(III) citrate of interest in a powdered state(yield: 25.86 kg; 78.86%).

Example 2

Iron(III) citrate of Example 2 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 165 minuteswhile maintaining the liquid temperature between 4.0° C. and 4.7° C.,and the final pH level was adjusted to 9.20 in the step of forming theiron-containing precipitate of Example 4 (yield: 136.03 kg, 85.3%).

Example 3

Iron(III) citrate of Example 3 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 165 minuteswhile maintaining the liquid temperature between 4.0° C. and 4.7° C.,and the final pH level was adjusted to 9.20 in the step of forming theiron-containing precipitate of Example 4 (yield: 136.42 kg, 84.7%).

Example 4 Step of Forming Iron-Containing Precipitate

An aqueous solution of ferric chloride (639.5 kg, 67.3 kg in terms ofFe³⁺, 1,205 mol) was introduced into a reaction vessel and diluted with1,002 kg of purified water to obtain an aqueous solution of ferricchloride containing 4.1% Fe³⁺ by weight. The aqueous solution of ferricchloride was cooled to a liquid temperature of 0° C. to 5° C. An aqueoussolution containing 10% NaOH by weight (1467.9 kg) that had been cooledto 0° C. to 5° C. in advance was added dropwise to the aqueous solutionof ferric chloride over a period of 120 minutes while maintaining theliquid temperature at 3.5° C. to 8.0° C., and the final pH level wasadjusted to 9.22. After the completion of dropwise addition, theobtained mixture was agitated at 3.7° C. to 4.7° C. (liquid temperature)for 1 hour. The pH level of the mixture was found to be between 8.0 and10.0.

Step of Washing

The mixture obtained in the step above was washed with 2,000 l ofpurified water with filtration. An iron-containing crude precipitatemainly composed of ferrihydride separated via filtration (i.e., a wetsolid (1), 628.02 kg) was agitated and washed in 1,627.0 kg of purifiedwater for 25 minutes. The suspension was filtered again to obtain aniron-containing precipitate mainly composed of ferrihydride (i.e., a wetsolid (2), 530.75 kg).

Step of Generating Aqueous Solution of Iron(III) Citrate

Citric acid (289.30 kg, 1,506 mol) was dissolved in 389.0 kg of purifiedwater to prepare an aqueous solution of citric acid (678.3 kg). The wetsolid (2) obtained in the step above (530.75 kg) and the aqueoussolution of citric acid above (678.3 kg) were introduced into a reactionvessel, and the mixture was prepared via slow agitation at roomtemperature (about 25° C.) for 69 minutes at an agitation speed of about50 rpm. Subsequently, the mixture was slowly heated to a temperature(liquid temperature) of 80° C. in such a manner that the differencebetween the temperature (liquid temperature) of the mixture and theexternal temperature was between 0° C. and 15° C. Thereafter, themixture was agitated at a liquid temperature of 80.0° C. to 81.9° C. for120 minutes to dissolve the iron-containing precipitate mainly composedof ferrihydride. After such dissolution had been confirmed, the mixturewas cooled to a liquid temperature of 20° C. to 30° C. Insolublematerial in the resulting mixture was removed by filtration to obtain anaqueous solution of iron(III) citrate (1,226.5 kg).

Step of Precipitating Iron(III) Citrate

Acetone (2,453 kg) was introduced into a reaction vessel. The aqueoussolution of iron(III) citrate obtained in the step above (613.2 kg) wasadded dropwise to acetone in the reaction vessel over a period of 45minutes with agitation. After the completion of dropwise addition, theobtained mixture was agitated at a liquid temperature of 24.0° C. to24.6° C. for 40 minutes. The resulting mixture was filtered to obtain aniron(III) citrate-containing precipitate (i.e., a wet solid (3), 425.17kg). The obtained wet solid (3) (425.17 kg) was dried to obtainhigh-purity iron(III) citrate of interest in a powdered state (yield:154.21 kg; 91.7%).

Example 5

Iron(III) citrate of Example 5 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 120 minuteswhile maintaining the liquid temperature between 3.5° C. and 8.0° C.,and the final pH level was adjusted to 9.22 in the step of forming theiron-containing precipitate of Example 4 (yield: 154.61 kg, 91.9%).

Example 6

Iron(III) citrate of Example 6 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 115 minuteswhile maintaining the liquid temperature between 2.6° C. and 7.5° C.,and the final pH level was adjusted to 9.09 in the step of forming theiron-containing precipitate of Example 4 (yield: 154.68 kg, 91.5%).

Example 7

Iron(III) citrate of Example 7 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 115 minuteswhile maintaining the liquid temperature between 2.6° C. and 7.5° C.,and the final pH level was adjusted to 9.09 in the step of forming theiron-containing precipitate of Example 4 (yield: 156.09 kg, 92.3%).

Example 8

Iron(III) citrate of Example 8 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 162 minuteswhile maintaining the liquid temperature between 2.4° C. and 8.6° C.,and the final pH level was adjusted to 9.21 in the step of forming theiron-containing precipitate of Example 4 (yield: 150.43 kg, 92.1%).

Example 9

Iron(III) citrate of Example 9 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 162 minuteswhile maintaining the liquid temperature between 2.4° C. and 8.6° C.,and the final pH level was adjusted to 9.21 in the step of forming theiron-containing precipitate of Example 4 (yield: 152.30 kg, 92.8%).

Example 10

Iron(III) citrate of Example 10 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 118 minuteswhile maintaining the liquid temperature between 2.6° C. and 7.6° C.,and the final pH level was adjusted to 9.13 in the step of forming theiron-containing precipitate of Example 4 (yield: 149.47 kg, 88.4%).

Example 11

Iron(III) citrate of Example 11 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 118 minuteswhile maintaining the liquid temperature between 2.6° C. and 7.6° C.,and the final pH level was adjusted to 9.13 in the step of forming theiron-containing precipitate of Example 4 (yield: 150.47 kg, 89.0%).

Example 12

Iron(III) citrate of Example 12 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 105 minuteswhile maintaining the liquid temperature between 0° C. and 7.3° C., andthe final pH level was adjusted to 8.98 in the step of forming theiron-containing precipitate of Example 4 (yield: 146.06 kg, 87.7%).

Example 13

Iron(III) citrate of Example 13 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 105 minuteswhile maintaining the liquid temperature between 0° C. and 7.3° C., andthe final pH level was adjusted to 8.98 in the step of forming theiron-containing precipitate of Example 4 (yield: 146.56 kg, 88.0%).

Example 14

Iron(III) citrate of Example 14 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 74 minuteswhile maintaining the liquid temperature between 1.3° C. and 8.3° C.,and the final pH level was adjusted to 8.91 in the step of forming theiron-containing precipitate of Example 4 (yield: 146.01 kg, 88.7%).

Example 15

Iron(III) citrate of Example 15 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 74 minuteswhile maintaining the liquid temperature between 1.3° C. and 8.3° C.,and the final pH level was adjusted to 8.91 in the step of forming theiron-containing precipitate of Example 4 (yield: 146.23 kg, 89.6%).

Example 16

Iron(III) citrate of Example 16 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 91 minuteswhile maintaining the liquid temperature between 2.5° C. and 8.4° C.,and the final pH level was adjusted to 9.64 in the step of forming theiron-containing precipitate of Example 4 (yield: 142.30 kg, 86.2%).

Example 17

Iron(III) citrate of Example 17 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 91 minuteswhile maintaining the liquid temperature between 2.5° C. and 8.4° C.,and the final pH level was adjusted to 9.64 in the step of forming theiron-containing precipitate of Example 4 (yield: 144.60 kg, 86.5%).

Example 18

Iron(III) citrate of Example 18 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 117 minuteswhile maintaining the liquid temperature between 1.9° C. and 8.0° C.,and the final pH level was adjusted to 8.40 in the step of forming theiron-containing precipitate of Example 4 (yield: 138.93 kg, 86.8%).

Example 19

Iron(III) citrate of Example 19 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 117 minuteswhile maintaining the liquid temperature between 1.9° C. and 8.0° C.,and the final pH level was adjusted to 8.40 in the step of forming theiron-containing precipitate of Example 4 (yield: 132.89 kg, 83.2%).

Example 20

Iron(III) citrate of Example 20 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 77 minuteswhile maintaining the liquid temperature between 1.4° C. and 8.3° C.,and the final pH level was adjusted to 8.61 in the step of forming theiron-containing precipitate of Example 4 (yield: 146.18 kg, 87.8%).

Example 21

Iron(III) citrate of Example 21 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 77 minuteswhile maintaining the liquid temperature between 1.4° C. and 8.3° C.,and the final pH level was adjusted to 8.61 in the step of forming theiron-containing precipitate of Example 4 (yield: 145.92 kg, 89.3%).

Example 22

Iron(III) citrate of Example 22 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 76 minuteswhile maintaining the liquid temperature between 2.2° C. and 9.1° C.,and the final pH level was adjusted to 9.08 in the step of forming theiron-containing precipitate of Example 4 (yield: 156.90 kg, 93.7%).

Example 23

Iron(III) citrate of Example 23 was prepared in the same manner as inExample 4, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 76 minuteswhile maintaining the liquid temperature between 2.2° C. and 9.1° C.,and the final pH level was adjusted to 9.08 in the step of forming theiron-containing precipitate of Example 4 (yield: 153.60 kg, 90.4%).

Example 24 Step of Forming Iron-Containing Precipitate

An iron-containing precipitate was obtained from the mixture prepared inthe same manner as in Example 4, except that an aqueous solution offerric chloride (186.2 g, 24.6 g in terms of Fe³⁺, 0.440 mol) was usedas a starting material, an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 100 minuteswhile maintaining the liquid temperature between 3.0° C. and 5.3° C.,and the final pH level was adjusted to 9.08. High-purity iron(III)citrate of interest was obtained (yield: 24.76 g, 90.6%) in the samemanner as in the step of generating an aqueous solution of iron(III)citrate and the step of precipitating iron(III) citrate of Example 4,except that the iron-containing precipitate divided into quarters wasused as a starting material and the amount of citric acid was equal tothat of Fe³⁺ in the step of generating an aqueous solution of iron(III)citrate.

Example 25

Iron(III) citrate of Example 25 was prepared in the same manner as inExample 20, except that the iron-containing precipitate obtained inExample 20 was used and the amount of citric acid was 2.50 times greaterthan that of Fe³⁺ in the step of generating an aqueous solution ofiron(III) citrate of Example 20 (yield: 26.79 g, 93.7%).

Example 26

Iron(III) citrate of Example 26 was prepared in the same manner as inExample 20, except that the iron-containing precipitate obtained inExample 20 was used and the amount of citric acid was 2.50 times greaterthan that of Fe³⁺ in the step of generating an aqueous solution ofiron(III) citrate of Example 20 (yield: 26.88 g, 93.8%).

Example 27

Iron(III) citrate of Example 27 was prepared in the same manner as inExample 20, except that the iron-containing precipitate obtained inExample 20 was used and the amount of citric acid was 3.00 times greaterthan that of Fe³⁺ in the step of generating an aqueous solution ofiron(III) citrate of Example 20 (yield: 27.96 g, 94.4%).

Example 28

Iron(III) citrate of Example 28 was prepared in the same manner as inExample 20, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 89 minuteswhile maintaining the liquid temperature between 2.3° C. and 6.3° C.,and the final pH level was adjusted to 9.13 in the step of formingiron-containing precipitate and the amount of citric acid was 1.10 timesgreater than that of Fe³⁺ in the step of generating an aqueous solutionof iron(III) citrate of Example 20 (yield: 37.05 g, 94.8%).

Example 29

Iron(III) citrate of Example 29 was prepared in the same manner as inExample 20, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 97 minuteswhile maintaining the liquid temperature between 0° C. and 5.9° C., andthe final pH level was adjusted to 9.25 in the step of formingiron-containing precipitate and the amount of citric acid was 1.25 timesgreater than that of Fe³⁺ in the step of generating an aqueous solutionof iron(III) citrate of Example 20 (yield: 37.98 g, 93.5%).

Example 30

Iron(III) citrate of Example 30 was prepared in the same manner as inExample 20, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 91 minuteswhile maintaining the liquid temperature between 3.1° C. and 6.3° C.,and the final pH level was adjusted to 9.21 in the step of formingiron-containing precipitate and the amount of citric acid was 1.40 timesgreater than that of Fe³⁺ in the step of generating an aqueous solutionof iron(III) citrate of Example 20 (yield: 37.15 g, 94.5%).

Example 31

Iron(III) citrate of Example 31 was prepared in the same manner as inExample 20, except that an aqueous NaOH solution was added dropwise tothe aqueous solution of ferric chloride over a period of 90 minuteswhile maintaining the liquid temperature between 3.7° C. and 5.4° C.,and the final pH level was adjusted to 9.28 in the step of formingiron-containing precipitate and the amount of citric acid was 1.55 timesgreater than that of Fe³⁺ in the step of generating an aqueous solutionof iron(III) citrate of Example 20 (yield: 37.69 g, 96.8%).

Comparative Examples 1-4

An iron(III) citrate was prepared in accordance with the methoddescribed in Patent Document 1. However, conditions of a stepcorresponding to the step of forming iron-containing precipitateaccording to the present invention were modified as shown in Table 3below.

Comparative Example 11

A commercially available iron(III) citrate for food additives was used(Kanto Kagaku; production lot number: 901×1445; date of production:January, 2007). Such iron(III) citrate is prepared by allowing ferricsulfate to react with ferric hydroxide prepared from ammonia water andwith citric acid, concentrating the resulting solution to prepare asyrup, applying the syrup thinly to a glass plate, and drying theresultant until a small lamina is peeled therefrom (the guidelines forJapanese Standards of Food Additives).

Comparative Example 12

A commercially available iron(III) citrate complying with food additivestandards was used (SIGMA, technical grade; production lot number:048K0125; date of production: June, 2008). Such iron(III) citrate isprepared in the same manner as described in Comparative Example 11.

2. Component Analysis of Iron(III) Citrate

The amount of iron(III) (via the titration method), the amount of citricacid (via liquid chromatography), and the amount of moisture (via theKarl Fischer method, coulometric titration; standard test code: B-021)were measured for iron(III) citrates of Comparative Examples 11 and 12and Examples 1 to 31 in accordance with conventional techniques. Theresults are shown in Table 1A and Table 1B.

TABLE 1A Results of component analysis of iron(III) citrates ofComparative Examples Comparative Amount of Amount of citric Amount ofwater Molar ratio of iron(III) Molar ratio of iron(III) Examplesiron(III) (wt. %) acid (wt. %) (wt. %) to citric acid to water 11 17.666.7 16.7 1:1.102 1:2.941 12 17.8 67.6 14.1 1:1.104 1:2.455 Average 17.767.2 15.4 1:1.10  1:2.70 

TABLE 1B Results of component analysis of iron(III) citrates of ExamplesAmount of Amount of citric Amount of water Molar ratio of iron(III)Molar ratio of iron(III) Examples iron(III) (wt. %) acid (wt. %) (wt. %)to citric acid to water 1 20.3 60.2 18.3 1:0.862 1:2.794 2 21.0 59.718.6 1:0.826 1:2.745 3 20.8 59.4 19.1 1:0.830 1:2.846 4 20.0 60.6 18.71:0.881 1:2.898 5 20.0 60.5 18.8 1:0.879 1:2.913 6 19.9 60.1 19.41:0.878 1:3.021 7 19.9 60.1 19.3 1:0.878 1:3.006 8 19.6 59.7 18.11:0.885 1:2.862 9 20.5 59.1 19.0 1:0.838 1:2.873 10 19.9 61.1 17.91:0.893 1:2.788 11 19.9 60.9 18.5 1:0.890 1:2.881 12 20.2 61.5 17.41:0.885 1:2.670 13 20.2 60.9 17.8 1:0.876 1:2.731 14 20.5 60.3 18.61:0.855 1:2.812 15 20.6 60.3 18.4 1:0.851 1:2.768 16 20.4 61.3 17.11:0.874 1:2.598 17 20.1 60.4 18.4 1:0.874 1:2.837 18 20.8 60.8 17.31:0.850 1:2.578 19 21.2 61.0 16.5 1:0.836 1:2.412 20 20.2 61.1 17.51:0.879 1:2.685 21 20.3 61.1 17.2 1:0.875 1:2.626 22 19.9 60.4 18.51:0.882 1:2.881 23 20.2 61.5 17.8 1:0.885 1:2.731 24 21.4 58.9 — 1:0.800— 25 18.1 65.6 — 1:1.054 — 26 18.3 65.8 — 1:1.045 — 27 17.6 66.5 —1:1.098 — 28 21.4 58.6 — 1:0.796 — 29 20.1 60.3 — 1:0.872 — 30 20.3 60.9— 1:0.872 — 31 20.0 61.5 — 1:0.894 — Maximum 21.4 66.5 19.4 1:1.0981:3.021 Minimum 17.6 58.6 16.5 1:0.796 1:2.412 Average 20.1 61.0 18.21:0.884 1:2.781

As shown in Table 1A, the average molar ratio of iron(III) to citricacid in iron(III) citrates of Comparative Examples 11 and 12 was 1:1.10,and the average molar ratio of iron(III) to water was 1:2.70.

In contrast, the amounts of iron(III), citric acid, and water iniron(III) citrates of Examples 1 to 31 were 17.6% to 21.4% by weight,58.6% to 66.5% by weight, and 16.5% to 19.4% by weight, respectively,based on the total weight of iron(III) citrate, as shown in Table 1B.That is, no remarkable differences were observed in the measurementresults for the examples. The molar ratio of iron(III) to citric aciddetermined based on the measured value above was 1:0.796 to 1:1.098, andthe molar ratio of iron(III) to water was 1:2.412 to 1:3.021.

The maximal and minimal molar ratios of Examples 1 to 31 were applied tothe molecular formula “Fe.x(C₆H₈O₇).y(H₂O).” As a result, the range of xwas found to be from 0.796 to 1.098, and that of y was found to be from2.412 to 3.021.

3. Elemental Analysis of Iron(III) Citrate

Iron(III) citrates of Comparative Examples 11 and 12 and Examples 1 to23 were subjected to elemental analysis in accordance with aconventional technique to measure the amount of carbon, the amount ofhydrogen, and the amount of oxygen. The results are shown in Table 2Aand Table 2B.

TABLE 2A Results of elemental analysis of iron(III) citrates ofComparative Examples Compositional Compositional Compositional Amount ofAmount of Amount of Amount of ratio of ratio of ratio of Comparativecarbon hydrogen oxygen iron(III)¹⁾ iron(III) to iron(III) to iron(III)to Examples (wt. %) (wt. %) (wt. %) (wt. %) carbon hydrogen oxygen 1125.1 3.5 52.1 17.6 1:6.63 1:11.02 1:10.33 12 26.0 3.3 51.3 17.8 1:6.791:10.27 1:10.06 Average 25.6 3.4 51.7 17.7 1:6.7  1:10.6  1:10.2 ¹⁾Values are reproduced from Table 1A “Amount of iron(III) (wt. %)”

TABLE 2B Results of elemental analysis of iron(III) citrates of ExamplesCompositional Compositional Compositional Amount of Amount of Amount ofratio of ratio of ratio of Amount of hydrogen oxygen iron(III)¹⁾iron(III) to iron(III) to iron(III) to Examples carbon (wt. %) (wt. %)(wt. %) (wt. %) carbon hydrogen oxygen  1 22.7 3.5 50.8 20.3 1:5.201:9.55 1:8.73  2 22.5 3.5 51.0 21.0 1:4.98 1:9.23 1:8.48  3 22.3 3.550.3 20.8 1:4.98 1:9.32 1:8.44  4 22.7 3.5 51.1 20.0 1:5.28 1:9.701:8.92  5 22.8 3.6 50.8 20.0 1:5.30 1:9.97 1:8.87  6 22.6 3.7 52.1 19.91:5.28  1:10.30 1:9.14  7 22.6 3.6 52.5 19.9 1:5.28  1:10.02 1:9.21  822.5 3.5 51.5 19.6 1:5.34 1:9.84 1:9.07  9 22.2 3.5 52.3 20.5 1:5.041:9.46 1:8.90 10 23.0 3.5 51.1 21.3 1:5.02 1:9.09 1:8.37 11 22.9 3.550.8 20.7 1:5.14 1:9.35 1:8.57 12 23.3 3.5 50.6 20.9 1:5.18 1:9.261:8.45 13 23.1 3.4 50.7 20.9 1:5.14 1:9.00 1:8.47 14 22.8 3.6 51.2 22.01:4.82 1:9.05 1:8.12 15 22.9 3.6 51.1 21.9 1:4.86 1:9.09 1:8.14 16 23.23.4 50.7 22.0 1:4.90 1:8.55 1:8.04 17 22.9 3.5 51.8 22.2 1:4.80 1:8.721:8.14 18 22.9 3.5 52.1 21.5 1:4.95 1:9.00 1:8.46 19 23.1 3.4 51.6 21.81:4.93 1:8.62 1:8.26 20 23.0 3.5 50.9 20.7 1:5.17 1:9.35 1:8.58 21 23.13.4 50.3 20.9 1:5.14 1:9.00 1:8.40 22 22.9 3.5 50.9 20.5 1:5.19 1:9.441:8.67 23 23.1 3.4 50.9 20.8 1:5.16 1:9.04 1:8.54 Maximum 23.3 3.7 52.522.2 1:5.34  1:10.30 1:9.21 Minimum 22.2 3.4 50.3 19.6 1:4.80 1:8.551:8.04 Average 22.8 3.5 51.2 20.9 1:5.09 1:9.30 1:8.56 ¹⁾Values ofExamples 1 to 9 are reproduced from Table 1B “Amount of iron(III) (wt.%)”

As shown in Table 2A, the average compositional ratio of iron(III) tocarbon, that of iron(III) to hydrogen, and that of iron(III) to oxygenin iron(III) citrates of Comparative Examples 11 and 12 were 1:6.7,1:10.6, and 1:10.2, respectively.

In contrast, the average compositional ratio of iron(III) to carbon,that of iron(III) to hydrogen, and that of iron(III) to oxygen iniron(III) citrates of Examples 1 to 23 were 1:5.09, 1:9.30, and 1:8.56,respectively, as shown in Table 2B. The above average compositionalratios were applied to the molecular formula “Fe.x(C₆H₈O₇).y(H₂O),”which is an embodiment of iron(III) citrate, the average composition wasdetermined to be “FeC_(5.09)H_(9.30)O_(8.56),” and the average molecularweight was determined to be 263.33.

4. Measurement of Infrared Absorption Spectrum of Iron(III) Citrate

The infrared absorption spectra (the IR spectra) of iron(III) citratesof Examples 1 to 23 were measured using the potassium bromide diskmethod. FIG. 1 shows the IR spectrum of iron(III) citrate of Example 4.

As shown in FIG. 1, the IR spectrum of iron(III) citrate according toExample 4 demonstrates that a strong absorption deduced to be derivedfrom C═O stretching vibration of dissociated carbonium ions of citricacid was observed at around 1,608 cm⁻¹ and a weak absorption deduced tobe derived from C═O stretching vibration of non-dissociative carboxylicacid of citric acid was observed at around 1,717 cm⁻¹. In addition,iron(III) citrates according to other examples exhibited IR spectralpatterns similar to those of the iron(III) citrate of Example 4, andabsorption bands of equivalent intensities were observed at regionsclose to the above wavelength regions.

5. Chemical Structure Analysis of Iron(III) Citrate

As described above, the results of component analysis, elementalanalysis, and infrared absorption spectral measurement demonstrate thatthe chemical structure of iron(III) citrates of Examples 1 to 31 is inthe form of a complex represented by the molecular formula:Fe.x(C₆H₈O₇).y(H₂O) (wherein x is from 0.796 to 1.098 and y is from2.412 to 3.021) instead of a normal salt in which the molar ratio ofiron(III) to trivalent citric acid is 1:1.

6. Powder X-Ray Diffraction Analysis of Iron(III) Citrate

Iron(III) citrate of Example 4 was subjected to powder X-ray diffractionanalysis to obtain a powder X-ray diffraction spectrum. Cobalt was usedas an anticathode. The results are shown in FIG. 2.

As shown in FIG. 2, the powder X-ray diffraction spectrum of iron(III)citrate of Example 4 exhibited a halo pattern having diffusive maxima.Accordingly, iron(III) citrate of Example 4 was determined to beamorphous (amorphous powder).

7. Identification of Beta-Iron Hydroxide Oxide and Quantification ofBeta-Iron Hydroxide Oxide

In order to qualitatively and quantitatively analyze beta-iron hydroxideoxides that are contaminants of the iron(III) citrates of Examples 1 to31, the peak area of the diffraction peak at around a diffraction angleof 40 to 41 degrees observed via powder X-ray diffraction (cobalt tube)was determined via the automatic integration method, and the amount ofbeta-iron hydroxide oxide (% by weight) relative to the total weight ofthe sample in an iron(III) citrate sample was determined via theexternal standard method using the formula:

amount of beta-iron hydroxide oxide (% by weight)=(Q_(T)/Q_(S))×0.025×CFwherein Q_(T) represents the peak area of the diffraction peak at arounda diffraction angle of 40 to 41 degrees derived from 2.5% beta-ironhydroxide oxide;

Q_(S) represents the peak area of the diffraction peak at around adiffraction angle of 40 to 41 degrees derived from the sample; and

CF represents the content of the standard beta-iron hydroxide oxide (%by weight).

Conditions for performing powder X-ray diffraction analysis are asdescribed below.

Target: Co

X-ray tube current: 40 mAX-ray tube voltage: 45 kVScan field: 2θ=38 to 44 degreesStep: 2θ=0.01671 degreesAverage time/step: 1000 sFixed divergence slit: ½ degreesRate of revolution: 60 rpmLight-receiving filter: Fe filterScan axis: GonioAnti-scatter slit: 1 degree

Test Example 1 Examination of Conditions for Sodium Hydroxide Addition

The influence of the temperature and the duration of sodium hydroxideaddition in the step of forming iron-containing precipitate on theproduction of beta-iron hydroxide oxide and on the solubility of theresulting iron(III) citrate was examined.

Iron(III) citrates of Examples 1 to 31 were prepared in accordance withthe method described in 1 above.

Iron(III) citrates of Comparative Examples 1 to 4 were prepared inaccordance with the method described in Patent Document 1 forcomparison.

Iron(III) citrates of Comparative Examples 1 to 4 and Examples 1 to 31were evaluated in terms of the presence or absence of a peak derivedfrom beta-iron hydroxide oxide via powder X-ray diffraction analysis,and solubility in the first fluid of dissolution testing of the JapanesePharmacopoeia, Fifteenth Edition after 30 minutes via the paddle methodaccording to the Japanese Pharmacopoeia, Fifteenth Edition (paddlemethod, 100 rpm, 600 mg/900 ml; ultraviolet and visible absorptionspectra of the solution are measured and determined based on absorptionat maximal wavelength). The results are shown in Table 3.

TABLE 3 Influence of temperature and duration of dropwise addition ofsodium hydroxide on generation of beta-iron hydroxide oxide and onsolubility of iron(III) citrate Evaluation of iron(III) citrateComparative Conditions for dropwise addition of sodium hydroxide Peakderived from beta-iron Examples/Examples Temperature Duration hydroxideoxide Solubility Comparative Example 1 26° C. to 28° C. 1 hour Observed82% Comparative Example 2 21° C. to 29° C. 1 hour and 40 minutesObserved 73% Comparative Example 3 21° C. to 29° C. 1 hour and 40minutes Observed 74% Comparative Example 4 22° C. to 24° C. 4 hoursObserved 79% Example 1  0° C. to 4.2° C. 2 hours Not observed 96%Example 2 4.0° C. to 4.7° C. 2 hours and 45 minutes Observed 93% Example3 4.0° C. to 4.7° C. 2 hours and 45 minutes Observed 94% Example 4 3.5°C. to 8.0° C. 2 hours Not observed 97% Example 5 3.5° C. to 8.0° C. 2hours Not observed 100%  Example 6 2.6° C. to 7.5° C. 1 hour and 55minutes Not observed 96% Example 7 2.6° C. to 7.5° C. 1 hour and 55minutes Not observed 97% Example 8 2.4° C. to 8.6° C. 2 hours and 42minutes Observed 94% Example 9 2.4° C. to 8.6° C. 2 hours and 42 minutesObserved 95% Example 10 2.6° C. to 7.6° C. 1 hour and 58 minutes Notobserved 88% Example 11 2.6° C. to 7.6° C. 1 hour and 58 minutes Notobserved 99% Example 12  0° C. to 7.3° C. 1 hour and 45 minutes Notobserved 99% Example 13  0° C. to 7.3° C. 1 hour and 45 minutes Notobserved 102%  Example 14 1.3° C. to 8.3° C. 1 hour and 14 minutes Notobserved 102%  Example 15 1.3° C. to 8.3° C. 1 hour and 14 minutes Notobserved 98% Example 16 2.5° C. to 8.4° C. 1 hour and 31 minutes Notobserved 95% Example 17 2.5° C. to 8.4° C. 1 hour and 31 minutes Notobserved 94% Example 18 1.9° C. to 8.0° C. 1 hour and 57 minutes Notobserved 97% Example 19 1.9° C. to 8.0° C. 1 hour and 57 minutes Notobserved 98% Example 20 1.4° C. to 8.3° C. 1 hour and 17 minutes Notobserved 100%  Example 21 1.4° C. to 8.3° C. 1 hour and 17 minutes Notobserved 98% Example 22 2.2° C. to 9.1° C. 1 hour and 16 minutes Notobserved 100%  Example 23 2.2° C. to 9.1° C. 1 hour and 16 minutes Notobserved 97% Example 24 3.0° C. to 5.3° C. 1 hour and 40 minutes Notobserved 94% Example 25 3.0° C. to 5.3° C. 1 hour and 40 minutes Notobserved 101%  Example 26 3.0° C. to 5.3° C. 1 hour and 40 minutes Notobserved 102%  Example 27 3.0° C. to 5.3° C. 1 hour and 40 minutes Notobserved 99% Example 28 2.3° C. to 6.3° C. 1 hour and 29 minutes Notobserved — Example 29  0° C. to 5.9° C. 1 hour and 37 minutes Notobserved — Example 30 3.1° C. to 6.3° C. 1 hour and 31 minutes Notobserved — Example 31 3.7° C. to 5.4° C. 1 hour and 30 minutes Notobserved —

In the step of forming iron-containing precipitate, the reaction betweenferric chloride and sodium hydroxide is preferably carried out at atemperature (liquid temperature) of 15° C. or lower, more preferably at10° C. or lower, and particularly preferably at 0° C. to 10° C., asshown in Table 3.

In the step of forming iron-containing precipitate, dropwise addition ofsodium hydroxide is preferably completed within 3 hours, more preferablywithin 2 hours, further preferably within 1 hour, and particularlypreferably within 30 minutes.

In the step of forming iron-containing precipitate, accordingly,dropwise addition of sodium hydroxide is preferably completed, forexample, within 3 hours at 15° C. or lower, 10° C. or lower, or 0° C. to10° C., more preferably within 2 hours at 15° C. or lower, furtherpreferably within 2 hours at 10° C. or lower, particularly preferablywithin 2 hours at 0° C. to 10° C. (liquid temperature), and mostpreferably within 1 hour at 0° C. to 10° C.

Test Example 2 Quantification of Beta-Iron Hydroxide Oxide

Regarding iron(III) citrates of Comparative Examples 1 to 4 and Examples1, 4, 5, 6, 7, and 10 to 23, the amount of beta-iron hydroxide oxide (%by weight) relative to the total weight of the sample in an iron(III)citrate sample was determined via powder X-ray diffraction analysisdescribed above. The results are shown in Table 4.

TABLE 4 Beta-iron hydroxide oxide content in iron(III) citrate Beta-ironhydroxide Lot number oxide content (wt. %) Iron(III) citrate ComparativeExample 1 6.8 produced by the Comparative Example 2 8.9 method of PatentComparative Example 3 8.3 Document 1 Comparative Example 4 7.3 Iron(III)citrate Example 1 Undetectable (1%) of the invention Example 4 Example 5Example 6 Example 7 Examples 10 to 23

8. Dissolution Profile in the First Fluid of Dissolution Testing of theJapanese Pharmacopoeia

The dissolution profiles of iron(III) citrates of Comparative Examples1, 11, and 12 and Examples 4, 5, 6, 7, 8, and 9 in the first fluid ofdissolution testing of the Japanese Pharmacopoeia, Fifteenth Edition (pH1.2) were compared via the paddle method according to the JapanesePharmacopoeia, Fifteenth Edition (paddle method, 100 rpm, 600 mg/900ml). The samples prepared in accordance with the method described abovewere grounded and used as iron(III) citrates of Comparative Example 1and Examples 4, 5, 6, 7, 8, and 9. The results are shown in FIG. 3.

According to an embodiment of the present invention, 95% by weight ormore of the iron(III) citrate dissolves in the first fluid ofdissolution testing of the Japanese Pharmacopoeia (pH 1.2, paddlemethod, 100 rpm, 600 mg/900 ml) within 15 minutes, and preferably within10 minutes, as shown in FIG. 3. In addition, the percentage dissolvedwithin 15 minutes is 80% or more, preferably 85% or more, morepreferably 90% or more, and most preferably 95% or more.

9. Measurement of Specific Surface Area

Specific surface areas of iron(III) citrates of Comparative Examples 11and 12 and Examples 1, 4, 5, 6, 7, and 10 to 23 were measured bynitrogen gas adsorption (relative pressure: 0.05 to 0.3) (BET surfacearea). The results are shown in Table 5.

TABLE 5 Specific surface area of iron(III) citrate Specific surface Lotnumber area (m²/g) Commercially available Comparative Example 11 0.80iron(III) citrate Comparative Example 12 0.62 Iron(III) citrate Example1 21.8 of the invention Example 4 33.4 Example 5 31.0 Example 6 30.4Example 7 29.8 Example 10 29.9 Example 11 30.0 Example 12 30.3 Example13 29.1 Example 14 37.9 Example 15 38.5 Example 16 33.7 Example 17 32.4Example 18 39.9 Example 19 39.8 Example 20 33.8 Example 21 35.5 Example22 32.6 Example 23 32.8

10. Pharmacological Test Use Example 1 Effects of Inhibiting PhosphorusAbsorption in Rats

Effects of the iron(III) citrate (Example 1) for inhibiting phosphorusabsorption were examined using rats. A feed mixture comprising theiron(III) citrate of Example 1 at 1.1% by weight or 3.2% by weight basedon the total weight of the feed mixture was administered to a group of 8or 9 male SD rats for 7 days. Feed containing no iron(III) citrate wasadministered to a control group. Rats were subjected to stool and urinesampling every day during administration. Phosphorus concentrations inthe stool and urine samples were measured, and the amounts of phosphorusexcreted into the stool and urine were determined. The amount determinedby subtracting the amount of iron(III) citrate from the amount of thefeed was multiplied by the phosphorus content in the feed to determinethe phosphorus intake, and the amount of phosphorus excreted into thestool was subtracted from the phosphorus intake to determine the amountof phosphorus absorbed. FIG. 4 shows the average amounts of phosphorusabsorbed and the average amounts of phosphorus excreted into the urineof the control group and of the test group (mg of phosphorus/day).

11. Test of Pharmaceutical Formulation Formulation Example 1 250-mgTablet

A graft copolymer of polyvinyl alcohol and polyethylene glycol (1.680kg, Kollicoat IR, BASF) and a copolymer of polyvinyl alcohol and methylacrylate or methyl methacrylate (0.42 kg, POVACOAT Type: F; DaidoChemical Industry Co., Ltd.) were added to 25.9 kg of purified water anddissolved with the aid of a propeller mixer to prepare a solution of abinder.

Iron(III) citrate (38.3248 kg, 30 kg in terms of anhydride, mixture of19.1624 kg each of iron(III) citrates produced in Examples 4 and 5) and3.4591 kg of crystalline cellulose (Ceolus, PH-102, Asahi KaseiChemicals Corporation) were introduced into a fluid bed granulator/dryer(WSG-60, Powrex Corp.), and 24.0 kg of the solution of the binder wassprayed for granulation, followed by drying. The resulting driedgranules were applied to a screen mill (model: U20, Powrex Corp.) to besifted through a screen (sieve mesh size: 1,143 μm). Thus,size-regulated powders were obtained.

Low-substituted hydroxypropylcellulose (3.42 kg, LH-11, Shin-EtsuChemical Co., Ltd.) and 0.57 kg of crospovidone (Kollidon CL-F, BASF)were added to 41.4048 kg of size-regulated powders obtained, and theresultant was mixed using a W-shaped blender (TCW-100, TokujuCorporation) at 29 rpm for 310 seconds. Subsequently, 0.7752 kg ofcalcium stearate (Japanese Pharmacopoeia grade, vegetable origin, TaiheiChemical Industrial Co. Ltd.) was added, and the resultant was mixedusing a W-shaped blender (TCW-100, Tokuju Corporation) at 29 rpm for 104seconds to obtain powders for tablet making. The powders for tabletmaking obtained were applied to a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho Ltd.) for tablet making at a tablet-makingpressure of 950 kgf/punch to obtain capsule-shaped, uncoated tabletswith a longer diameter of 14.8 mm, a shorter diameter of 6.8 mm, and amass of 405 mg.

The resulting uncoated tablets (12.15 kg) were coated with a coatingliquid obtained by mixing 600 g of hypromellose (TC-5M, Shin-EtsuChemical Co., Ltd.), 200 g of titanium oxide (titanium(IV) oxide extrapure, Merck), 100 g of talc (Hi-Filler #17, Matsumura Sangyo Co., Ltd.),100 g of Macrogol 6000 (Macrogol 6000P, NOF Corporation), and 7,000 g ofpurified water using an automatic coating machine (HCT-60N, FreundCorporation). Thus, tablets each coated with a film of about 18 mg wereobtained (each tablet comprising 12 mg of a graft copolymer of polyvinylalcohol and polyethylene glycol, 3 mg of a copolymer of polyvinylalcohol and methyl acrylate or methyl methacrylate, 30 mg oflow-substituted hydroxypropylcellulose, and 5 mg of crospovidone).

Compositions of the uncoated tablets and tablets coated with films ofPreparation Example 1 are shown in Table 6.

TABLE 6 Composition of Preparation Example 1 Component Amount(mg/tablet) Iron(III) citrate (mixture of Example 4 319.4 and Example 5)(Weight in terms of anhydride) (250.0) Crystalline cellulose 28.8 Graftcopolymer of polyvinyl alcohol and 12.0 polyethylene glycol Copolymer ofpolyvinyl alcohol and methyl 3.0 acrylate or methyl methacrylateLow-substituted hydroxypropylcellulose 30.0 Crospovidone 5.0 Calciumstearate 6.8 Total of uncoated tablets (weight including 405.0 moisturein iron(III) citrate) (Weight excluding moisture in iron(III) citrate)(335.6) Hypromellose 10.8 Titanium oxide 3.6 Talc 1.8 Macrogol 6000 1.8Total of tablets coated with films 18.0

INDUSTRIAL APPLICABILITY

The method of the present invention can provide iron(III) citrate with areduced beta-iron hydroxide oxide content and high-purity iron(III)citrate exhibiting excellent dissolution properties.

1. High-purity iron(III) citrate substantially free of beta-ironhydroxide oxide, wherein the beta-iron hydroxide oxide content is lessthan 6% by weight based on the total weight thereof.
 2. The high-purityiron(III) citrate according to claim 1, wherein the beta-iron hydroxideoxide content is less than 2.5% by weight.
 3. The high-purity iron(III)citrate according to claim 1, wherein the beta-iron hydroxide oxidecontent is less than 1.0% by weight.
 4. The high-purity iron(III)citrate according to claim 1, wherein the molar ratio of iron(III) tocitric acid is from 1:0.75 to 1:1.10.
 5. The high-purity iron(III)citrate according to claim 4, wherein the molar ratio of iron(III) tocitric acid is from 1:0.80 to 1:0.92.
 6. The high-purity iron(III)citrate according to claim 1, wherein the percentage of iron(III)citrate dissolved within 15 minutes is 80% or more in dissolutiontesting conducted with the use of the first fluid of dissolution testingof the Japanese Pharmacopoeia, Fifteenth Edition as a test liquid viathe paddle method at 100 rpm in accordance with the JapanesePharmacopoeia, Fifteenth Edition.
 7. A pharmaceutical compositioncomprising, as an active ingredient, the high-purity iron(III) citrateaccording to claim
 1. 8. A method of treating hyperphosphatemia,comprising administering the high-purity iron(III) citrate according toclaim 1 to a subject in need thereof.
 9. Powder of the high-purityiron(III) citrate according to claim 1, which has an amorphousstructure.
 10. Powder of the high-purity iron(III) citrate according toclaim 1, which has a specific surface area of 20 to 45 m2/g.
 11. Powderof the high-purity iron(III) citrate according to claim 9, which has aspecific surface area of 20 to 45 m2/g.
 12. A pharmaceutical compositioncomprising, as an active ingredient, the powder according to claim 9.13. A method of treating hyperphosphatemia, comprising administering thepowder according to claim 9 to a subject in need thereof.
 14. A methodfor producing iron(III) citrate comprising: a step of forming aniron-containing precipitate comprising bringing ferric chloride intocontact with sodium hydroxide for a short period of time at lowtemperature in an aqueous medium to form an iron-containing precipitate;a step of generating an aqueous solution of iron(III) citrate comprisingbringing citric acid into contact with the iron-containing precipitatein an aqueous medium and generating an aqueous solution of iron(III)citrate via heating; and a step of precipitating iron(III) citratecomprising bringing the aqueous solution of iron(III) citrate intocontact with an organic solvent to precipitate the iron(III) citrate.15. The method according to claim 14, wherein the step of formingiron-containing precipitate comprises bringing ferric chloride intocontact with sodium hydroxide within 2 hours at a liquid temperature of0° C. to 10° C.
 16. The method according to claim 14, wherein the stepof generating an aqueous solution of iron(III) citrate comprisesbringing citric acid into contact with the iron-containing precipitateat a liquid temperature of 60° C. to 100° C.
 17. The method according toclaim 14, wherein the iron-containing precipitate is ferrihydride. 18.Iron(III) citrate produced by the method according to claim
 14. 19. Apharmaceutical composition comprising, as an active ingredient, theiron(III) citrate according to claim
 18. 20. A method of treatinghyperphosphatemia, comprising administering the iron(III) citrateaccording to claim 18 to a subject in need thereof.
 21. Powder of theiron(III) citrate according to claim 18, which has an amorphousstructure.
 22. Powder of the iron(III) citrate according to claim 18,which has a specific surface area of 20 to 45 m2/g.
 23. Powder of theiron(III) citrate according to claim 21, which has a specific surfacearea of 20 to 45 m2/g.
 24. A pharmaceutical composition comprising, asan active ingredient, the powder according to claim
 21. 25. A method oftreating hyperphosphatemia, comprising administering the powderaccording to claim 21 to a subject in need thereof.
 26. A method oftreating hyperphosphatemia, comprising administering the pharmaceuticalcomposition according to claim 7 to a subject in need thereof.